We have recently shown that plasma beta-endorphin and adrenocorticotropic hormone (ACTH) are increased in experimental right heart failure, and that acute administration of opiate receptor antagonists increases cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to the skeletal muscle, myocardium, and kidneys. We have further shown that the acute salutary hemodynamic effects are mediated via delta-receptor mediated sympathetic stimulation. These results indicate that endogenous opioid peptides may play an important role in the regulation of circulations in chronic heart failure and that their actions depend on the functional integrity of the beta-adrenoceptor-coupled adenylate cyclase activity. We propose to study the effects of chronic opiate receptor inhibition in heart failure. We speculate that since excessive sympathetic stimulation in heart failure reduces myocardial beta-receptor number and adenylate cyclase activity (probably secondary to alterations in guanine nucleotide-binding proteins) the adrenergically-mediated stimulatory effects associated with the initial administrations of opiate receptor blockers may be lost with time during chronic opiate receptor inhibition, and a worsening of myocardial function ensues. We will administer naltrexone, an orally active long-acting opiate receptor blocking agent, or placebo, for 6 weeks either during the development of heart failure or after stable heart failure has developed, to determine whether chronic opiate receptor inhibition enhances the onset or the degree of beta- adrenoceptor down-regulation, beta-adrenergic sensitivity, guanine nucleotide-binding proteins, and myocardial failure. We will measure the resting and exercise hemodynamics, plasma beta-endorphin, ACTH and catecholamines, baroreflex sensitivity, and inotropic left ventricular responses to adrenergic agents at the start and end of treatment. WE will measure myocardial norepinephrine, beta-adrenoceptor density, adenylate cyclase activity, levels of guanine nucleotide-binding proteins, and right ventricular contractile function using an isolated trabeculate muscle preparation. Results of the study will further our understanding of the role of endogenous opioids in the circulation of heart failure, and may potentially lead to new treatments for heart failure.
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